Hypertonic Dextran Solution and Methods of Treating and Preventing Recurrent Corneal Erosion

ABSTRACT

An ophthalmic solution is provided. The ophthalmic solution is hypertonic. The ophthalmic solution includes a polysaccharide having an average molecular weight of between about 40,000 grams per mole and about 150,000 grams per mole. A packaged ophthalmic solution for preventing the ophthalmic solution from being exposed to CO 2  and other contaminants is also provided. The ophthalmic solution can be used to treat recurrent corneal erosion. The ophthalmic solution can also be used as a prophylactic to prevent recurrent corneal erosion.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of U.S. application Ser. No. 13/200,270,filed on Sep. 22, 2011, pending, the entire disclosure of which ishereby expressly incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to an ophthalmic hypertonic compositionincluding a water-soluble polysaccharide of glucose having an averagemolecular weight of between about 40,000 and about 150,000 grams permole. The ophthalmic composition can be used to treat recurrent cornealerosion. The ophthalmic composition can also be used as a prophylacticto prevent recurrent corneal erosion. The present invention also relatesto a packaging for the ophthalmic composition.

BACKGROUND OF THE INVENTION

It is important for the cornea to be transparent with an opticallysmooth surface for the formation of a sharp visual image on the retina.The normal, healthy cornea is transparent, mostly acellular connectivetissue consisting of collagen fibers and mucopolysaccharides. Thistissue is called the stroma, which is covered by several layers ofepithelial cells on the exterior surface, while its interior surface iscovered with a single layer of endothelial cells. The macromolecules ofthe stroma form a loosely connected matrix that contains about 80% byweight of aqueous fluid. This interstitial fluid of the stroma is nearlyisotonic. The tissue, however, behaves as if it were somewhatdehydrated, since it tends to imbibe, i.e. absorb, additional fluid whenimmersed in physiological saline. This occurs because the additionalosmolality of its macromolecular matrix causes a net flow of water intothe stroma by osmosis, with the epithelium acting as a semipermeablemembrane. This tendency of water absorption is measured in terms of theso-called “imbibition pressure,” which is about 40-60 torr for thenormal cornea. As the degree of hydration of the stroma increases, theimbibition pressure diminishes. Active transport of electrolytes andthus water out of the stroma by its boundary layers of cells keeps thestromal hydration at its normal, i.e. somewhat dehydrated, level inorder to maintain its transparency. As the cornea imbibes water, itbecomes progressively more cloudy diminishing visual acuity. A highlyedematous cornea scatters so much light that it appears to be quiteopaque.

Recurrent corneal erosion (RCE) is the recurrence of corneal erosions,either dystrophic or post-traumatic, not precipitated by nor associatedwith a dry eye condition. RCE can cause the cornea to be edematous. RCEcan be a painful and disabling condition of the cornea that causesconsiderable interference with visual function due to pain, transientdecreased vision, and light sensitivity and anxiety, and often resultsin patients becoming incapacitated and limited in their dailyactivities. RCE often develops as a result of three different issues:diabetic keratrophy; neurotrophic keratrophy; and following eye surgerysuch as Lasik surgery.

Symptomatic treatment of RCE with existing hypertonic salt solutions hasbeen ineffective, or even harmful, since the solute of the solution canreadily penetrate the stroma achieving hypertonic levels inside thetissue which causes further imbibition of water with the resultingclouding of the cornea which diminishes visual acuity. Additionally,most patients do not respond to treatment with patching or topicallubricants. Some patients may receive temporary relief, but the cornealerosion recurs, resulting in further pain, transient decreased vision,and light sensitivity.

A need therefore exists for an ophthalmic composition that can be usedto effectively treat RCE once it has occurred.

A need also exists for an ophthalmic composition that will act as aprophylactic to prevent RCE from occurring, especially for people whoare at an increased risk for developing RCE.

A need further exists for packaged ophthalmic solutions that willmaintain the stability of ophthalmic compositions for preventing andtreating RCE.

BRIEF SUMMARY OF THE INVENTION

The present invention provides ophthalmic solutions, and packagedophthalmic solutions for preventing and for treating RCE. In addition,methods of treating RCE using ophthalmic solutions, and methods ofpreventing RCE using ophthalmic solutions are provided.

In one aspect of the invention, an ophthalmic solution for bothpreventing and for treating RCE is provided. In particular, theophthalmic solution comprises between about 5% and 25% by weight of apolymer of glucose having an average molecular weight of between about40,000 grams per mole and about 150,000 grams per mole; between about0.5% and 2% by weight NaCl; between about 0.5% and 2% by weighthyaluronic acid; and between about 71% and 94% by weight distilledwater. The ophthalmic solution has a pH between about 6.5 and 7.5, hasan osmotic pressure of between about 320-350 mOsmol/kg solution, and ishypertonic. Typically, for relatively long-term storage (e.g., more than30 days), it is desired for the solution to contain a buffer and/or from0 to less than about 360 ppm CO₂, more desirably less than about 100 ppmCO₂, by weight of the total composition.

In another embodiment, the polymer of glucose is dextran, which may havean average molecular weight of in the range of from about 60,000 to80,000 grams per mole and preferably about 70,000 grams per mole.

In another embodiment, the ophthalmic solution contains between about 8%and 12% by weight of dextran.

In one aspect of the invention, a packaged ophthalmic solution productis provided. It has been discovered that the addition of contaminants,such as CO₂, into the composition, such as from the atmosphere, wouldchange the pH and effectiveness of ophthalmic compositions in accordancewith the invention. The packaged ophthalmic solution comprises a plasticampoule containing an ophthalmic solution. The ophthalmic solutioncontained within the plastic ampoule comprises between about 5% and 25%by weight of a polymer of glucose having an average molecular weight ofbetween about 40,000 grams per mole and about 150,000 grams per mole;between about 0.5% and 2% by weight NaCl; between about 0.5% and 2% byweight hyaluronic acid; between about 71% and 94% by weight distilledwater; and from 0 to less than about 360 ppm CO₂, more desirably lessthan 100 ppm CO₂, by weight of the total composition. The ophthalmicsolution of the invention is hypertonic. The packaged ophthalmicsolution also includes a foil pouch that provides an effective barrierto prevent transport of CO₂ therethrough and into the solution. The foilalso prevents transport of water from the solution to the atmosphere.The plastic ampoule is contained and sealed within the foil pouch.

In one embodiment, the foil pouch prevents air, including carbon dioxide(CO₂) and oxygen (O₂) from entering the plastic ampoule. Additionally,the foil pouch prevents liquid from exiting the plastic ampoule to theatmosphere.

In another aspect of the invention, a method of treating recurrentcorneal erosion is provided. An ophthalmic solution is topicallyadministered to the eye. The ophthalmic solution comprises between about5% and 25% by weight of a polymer of glucose having an average molecularweight of between about 40,000 grams per mole and about 150,000 gramsper mole; between about 0.5% and 2% by weight NaCl; between about 0.5%and 2% by weight hyaluronic acid; and between about 71% and 94% byweight distilled water. The ophthalmic solution also has a pH betweenabout 6.5 and 7.5, has an osmotic pressure of between about 320-350mOsmol/kg solution, and is hypertonic. The ophthalmic solution isadministered about every 3 to 8 hours for about 2 to 12 weeks.

In one embodiment, the polymer of glucose is dextran, which may have anaverage molecular weight of in the range of from about 60,000 to 80,000grams per mole and preferably about 70,000 grams per mole. Theophthalmic solution may also comprise between about 8% and 12% by weightof dextran.

In another embodiment, the ophthalmic solution further comprises apreservative. Specifically, the ophthalmic solution may comprisethimerosal and/or EDTA.

In a further embodiment, the ophthalmic solution is administered aboutevery 3 to 4 hours for about 7 to 10 weeks.

In another aspect of the invention, a method of preventing RCE isprovided. An ophthalmic solution is topically administered to the eye.The ophthalmic solution comprises between about 5% and 25% by weight ofa polymer of glucose having an average molecular weight of between about40,000 grams per mole and about 150,000 grams per mole; between about0.5% and 2% by weight NaCl; between about 0.5% and 2% by weighthyaluronic acid; between about 71% and 94% by weight distilled water;and from 0 to less than about 360 ppm CO₂, more desirably less thanabout 100 ppm CO₂, by weight of the total composition. The ophthalmicsolution of the invention has a pH between about 6.5 and 7.5, has anosmotic pressure of between about 320-350 mOsmol/kg solution, and ishypertonic. Optionally, a suitable buffer may be included.

In one embodiment, the ophthalmic solution of the invention is obtainedfrom the packaged ophthalmic solution of the invention within about 4days prior to the administering.

In a specific embodiment, the ophthalmic solution is administered aboutevery 3 to 8 hours for about 7 to 14 days prior to an eye surgery.

In another embodiment, the ophthalmic solution is administered aboutevery 3 to 4 hours for about 10 days prior to an eye surgery.

In a further embodiment, the ophthalmic solution is administered aboutevery 3 to 8 hours for about 7 to 14 days following an eye surgery.

In another embodiment, the ophthalmic solution is administered at leastone time per day to prevent recurrent corneal erosion as a result ofdiabetic keratrophy.

In another embodiment, the ophthalmic solution is administered at leastone time per day to prevent recurrent corneal erosion as a result ofneurotrophic keratrophy.

In one embodiment, the polymer of glucose is dextran. The dextran mayhave an average molecular weight in the range of from about 60,000 toabout 80,000 grams per mole and preferably about 70,000 grams per mole.The ophthalmic solution may also comprise between about 8% and 12% byweight of the dextran.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a packaged ophthalmic product in accordancewith the invention.

FIG. 2 is an illustration of a foil pouch in accordance with theinvention.

FIG. 3 is a detailed drawing of one embodiment of an ampoule packaged ina foil pouch in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

The ophthalmic composition of this invention can be used to treat RCE.The ophthalmic composition can also be used to prevent RCE fromoccurring.

A typical colloidal component for use in the ophthalmic solution of thepresent invention is a polymer of glucose that is chiefly joined throughα-1,6-glycosidic linkages, such as dextran, that is obtained byappropriate processing of the high molecular weight product derived fromthe fermentation of sucrose by the bacteria Leuconostoc mesenteroides.Dextran has the molecular formula:

The dextran component of the ophthalmic solution has an averagemolecular weight of at least about 40,000 and not more than about150,000 grams per mole, more typically or preferably from about 60,000to about 80,000 grams per mole and most preferably about 70,000 gramsper mole and is obtained by partial hydrolysis and fractionation of thehigh molecular weight fermentation product. This polysaccharide ishighly water-soluble forming aqueous solutions of low viscosity, andcarries no net electric charge. The effect of dextran on water surfacetension is negligible.

Typically, the ophthalmic solution contains between about 5% and 25% byweight dextran. More typically, the ophthalmic solution contains betweenabout 8% and 12% by weight dextran. Preferably, the ophthalmic solutioncontains about 10% by weight dextran.

Another hydrophilic polymer useful as the colloidal component of theophthalmic solution of the present invention is the synthetic polymerpolyacrylamide having an average molecular weight between about 20,000and about 150,000 grams per mole. This polymer is also highlywater-soluble forming aqueous solutions of low viscosity, carries no netelectric charge, and has a negligible effect on water surface tension.

Aqueous solutions of dextran and polyacrylamide are highly stable andare compatible with the naturally occurring biopolymers found in tears.Both polymers have very low toxicity. Additionally, both polymers arenonionic, and thus the concentration of inorganic salts needed toachieve physiological tonicity has no appreciable deleterious effect ontheir solubility so that polymer solutions at concentration levelsneeded to achieve and even surpass the colloidal osmolality of thedeturgescent cornea can readily be formulated even in the presence ofinorganic electrolytes.

Preferably, the ophthalmic solution is hypertonic. The ophthalmicsolution is formulated to provide a colloidal osmotic concentrationslightly greater than the corneal swelling pressure.

Additionally, the ophthalmic solution has an osmolality of between about320 and 350 mOsm/kg. Typically, the ophthalmic solution has anosmolality of between about 325 and 345 mOsm/kg. Most typically, theophthalmic solution has an osmolality of about 335 mOsm/kg.

The ophthalmic solution may also contain any useful salts, such as, forexample, sodium chloride, potassium chloride, calcium chloride,magnesium chloride, and various sulfates, phosphates, borates, nitrates,citrates, acetates, etc.

Typically, the ophthalmic solution contains between about 0.5% and 2% byweight NaCl. More typically, the ophthalmic solution contains betweenabout 0.7% and 1.2% by weight NaCl. Preferably, the ophthalmic solutioncontains about 0.9% by weight NaCl.

The ophthalmic solution may also contain hyaluronic acid. Hyaluronicacid is an anionic, nonsulfated glycosaminoglycan that is naturallydistributed widely throughout connective, epithelial, and neural tissuesof the human body. Hyaluronic acid is a polymer of disaccharides, linkedvia alternating β-1,4 and β-1,3 glycosidic bonds. Hyaluronic acid can be25,000 disaccharide repeats in length, and has the molecular formula:

Polymers of hyaluronic acid can range in size from 5,000 to 20,000,000grams per mole.

Typically, the ophthalmic solution contains between about 0.5% and 2% byweight hyaluronic acid. More typically, the ophthalmic solution containsbetween about 0.75% and 1.5% by weight hyaluronic acid. Most typically,the ophthalmic solution contains about 1% by weight hyaluronic acid.

Hyaluronic acid increases the lubricity of the ophthalmic solution. Thecombination of the hyaluronic acid and the dextran in the ophthalmicsolution improves the function of the solution in drawing out fluidbetween the epithelial and basement layers of an eye.

Additionally, the ophthalmic solution may contain a preservative.Preservatives may include, for example, biocides such as benzalkoniumchloride, thimerosal, phenylmercuric nitrate, chlorobutanol, methylparaben, propyl paraben, chlorhexidine digluconate, and sorbic acid andchelating agents, such as for example, di, tri, or tetrasodium ethylenediamine tetraacetate, also known as edetates, may be added atconcentrations between about 0.001% and 0.1% by weight. Typically, theophthalmic composition contains thimerosal and/orethylenediaminetetraaceticacid (EDTA).

The ophthalmic solution may also contain a buffer or buffering agent tomaintain pH, as described herein.

In addition, the ophthalmic solution of the present invention can alsocontain an eye compatible anesthetic such as, for example, benoxinate,butyl-4-amino-benzoate, naepaine, and phenacaine.

Furthermore, the ophthalmic solution of the present invention may alsobe used as a carrier for ophthalmic medicants, for example: mydriaticssuch as tropicamide, atropine, and epinephrine; miotics such aspilocarpine and carbachol; cycloplegics such as cyclopentolate;anti-inflammatories such as dexamethasone and prednisolone;anti-infectives such as sulfas and antibiotics; and vasoconstrictorssuch as phenylephrine and naphazoline. The medicants may be present inthe form of their pharmaceutically acceptable salts or esters.

Another optional ingredient of the ophthalmic solution of the presentinvention is an eye compatible fluorescing compound of the type used influorophotometric determinations such as that used when fitting contactlens. Examples of such fluorescing compounds include sodium fluoresceinand fluorexon.

The balance of the ophthalmic solution is distilled water. Typically,the ophthalmic solution contains between about 71% and 94% by weightdistilled water. Most typically, the ophthalmic solution containsbetween about 88% and 90% by weight distilled water.

The ophthalmic solution typically has a pH of between about 6.5 and 7.5.More typically, the ophthalmic solution has a pH of between about 6.8and 7.2. Most typically, the ophthalmic solution has a pH of about 7.0.A buffer may be included to maintain or help maintain the pH in theforegoing ranges.

The ophthalmic solution has a viscosity of between about 6.5 and 7.5centistokes. Typically, the ophthalmic solution has a viscosity ofbetween about 6.8 and 7.2 centistokes. Most typically, the ophthalmicsolution has a viscosity of about 7.0 centistokes.

Typically, the ophthalmic solution in accordance with the inventioncontains less than about 360 ppm carbon dioxide, more desirably lessthan about 100 ppm CO₂, all by weight of the total ophthalmiccomposition.

The ophthalmic solution is formulated to provide a colloidal osmoticconcentration slightly greater than the corneal swelling pressure.Topical application of such a solution could diminish or control basaland subepithelial edema that interferes with the adhesion of epithelialcells while providing an effective lubricating layer to the surface ofthe eye, preventing abrasive sheer forces from the lid margin duringblinking.

A packaged ophthalmic solution 10 in accordance with the invention isgenerally illustrated in FIGS. 1-3 and is composed of ophthalmicsolution 11, plastic ampoules 12 a-e which contain the ophthalmicsolution 11 and foil pouch 18 which contains ampoules 12 a-e. Asillustrated in FIG. 1, packaged ophthalmic solution 10 comprises plasticampoules 12 a-e and the ophthalmic solution as described previouslycontained therein. Any type of plastic that is suitable for storing theophthalmic solution of the invention may be utilized. Packagedophthalmic solution 10 is stored within plastic ampoules 12 a-e. Theplastic ampoules 12 a-e as configured include and are connected to eachother by side connectors 14 a-d. Side connectors 14 a-d are designed toallow an individual plastic ampoule 12 a-e to be individuallydisconnected from packaging 10. Each plastic ampoule 12 a-e includes atop 16 a-e. Tops 16 a-e are designed to be disconnected from plasticampoules 12 a-e upon preparation of administration of the ophthalmicsolution. Alternatively, it is to be understood that in place of plasticampoules 12 a-e could be some other type of individual plastic or othersuitable container for the ophthalmic solution of the invention, suchas, for example, multiple dose or single dose plastic bottles or pouchesor some other plastic container as desired. Such containers, whileproviding adequate short-term storage and resistance to penetration byCO₂, for example, are not suitable for longer term (i.e., more than 30days or more) resistance to CO₂ penetration and consequently would besealed within a foil container or pouch, such as pouch 18. Foil pouch 18also prevents transport of water from the solution into the atmosphere.

Plastic ampoules 12 a-e are each appropriately sized to contain a singledose of the ophthalmic solution. Typically, a single dose of theophthalmic solution is between about 0.2 and 0.5 mL. More typically, asingle dose of the ophthalmic solution is between about 0.25 and 0.4 mL.Most typically, a single dose of the ophthalmic solution is about 0.3mL.

As illustrated in FIGS. 1-3, packaged ophthalmic solution 10 includesfoil pouch 18. Foil pouch 18 can be of any suitable shape andconfiguration as long as it provides the desired impenetrability to CO₂.Foil pouch 18 is crimp sealed to prevent unwanted exposure to gases,such as CO₂ or air, which, of course, contains CO₂, from passing throughand contacting ophthalmic solution 11. The passage of CO₂ throughplastic ampoules 12 a-e and into ophthalmic solution 11 would alter thepH of ophthalmic solution 11 contained within plastic ampoules 12 a-e,resulting in a composition that is too acidic. Foil pouch 18 alsoprevents liquid (i.e., water) from passing through plastic ampoules 12a-e to the atmosphere. The foil should be of a thickness, type and besuitably sealed to prevent passage of any significant amounts (amountsthat would be deleterious to the stored solution) of CO₂ and/or waterthrough the foil package so as to adequately preserve the storedsolution.

The solution in accordance with the invention may also be buffered, inwhich case absorption of CO₂, such as from the atmosphere would notnormally be of concern. Suitable buffers include borates, sorbates,phosphates, citrates, carbonates and ascorbates. The amount of bufferwill be sufficient under normal circumstances to maintain the pH in arange of from about 6.5 to about 7.5. Suitable amounts of bufferingagents may be in the range of 0.05 to 2 mmol (HCl)/L.

Another aspect of the present invention relates to a method of treatingRCE. As used herein, the term “treating” refers to: (i) relieving adisease, disorder or condition, i.e., causing regression of the disease,disorder and/or condition; and/or (ii) inhibiting a disease, disorder orcondition, i.e., arresting its development.

The method of treating RCE comprises topically administering to an eyean ophthalmic solution as described herein, the ophthalmic solutioncomprising: between about 5% and 25% by weight of a polymer of glucosehaving an average molecular weight of between about 40,000 grams permole and about 150,000 grams per mole; between about 0.5% and 2% byweight NaCl; between about 0.5% and 2% by weight hyaluronic acid; andbetween about 71% and 94% by weight distilled water. The ophthalmicsolution has a pH between about 6.5 and 7.5, has an osmotic pressure ofbetween about 320-350 mOsmol/kg solution, and is hypertonic.

Additionally, the ophthalmic solution may contain a preservative.Preservatives may include, for example, biocides such as benzalkoniumchloride, thimerosal, phenylmercuric nitrate, chlorobutanol, methylparaben, propyl paraben, chlorhexidine digluconate, and sorbic acid andchelating agents, such as for example, di, tri, or tetrasodium ethylenediamine tetraacetate, also known as edetates, may be added atconcentrations between about 0.001% and 0.1% by weight. Typically, theophthalmic solution contains thimerosal and/or ethylene diaminetetraacetic acid (EDTA).

In addition, the ophthalmic solution can also contain an eye compatibleanesthetic such as, for example, benoxinate, butyl-4-amino-benzoate,naepaine, and phenacaine.

Furthermore, the ophthalmic solution may also be used as a carrier forophthalmic medicants, for example: mydriatics such as tropicamide,atropine, and epinephrine; miotics such as pilocarpine and carbachol;cycloplegics such as cyclopentolate; anti-inflammatories such asdexamethasone and prednisolone; anti-infectives such as sulfas andantibiotics; and vasoconstrictors such as phenylephrine and naphazoline.The medicants may be present in the form of their pharmaceuticallyacceptable salts or esters.

Another optional ingredient of the ophthalmic solution is an eyecompatible fluorescing compound of the type used in fluorophotometricdeterminations such as that used when fitting contact lens. Examples ofsuch fluorescing compounds include sodium fluorescein and fluorexon.

The ophthalmic solution is topically administered about every 3 to 8hours for about 2 to 16 weeks. Typically, the ophthalmic solution may beadministered about every 4 to 6 hours for about 6 to 12 weeks.

The ophthalmic solution may be administered about 3 to 10 times dailyfor about 2 to 12 weeks. More typically, the ophthalmic solution isadministered at least 5 times daily for at least 8 weeks.

Another aspect of the present invention relates to a method ofpreventing RCE. As used herein, the term “preventing” refers topreventing a disease, disorder or condition from occurring in a subjectthat may be predisposed to the disease, disorder and/or condition buthas not yet been diagnosed as having it.

The method of preventing RCE comprises topically administering to an eyean ophthalmic solution as described herein, the ophthalmic solutioncomprising: between about 5% and 25% by weight of a polymer of glucosehaving an average molecular weight of between about 40,000 grams permole and about 150,000 grams per mole; between about 0.5% and 2% byweight NaCl; between about 0.5% and 2% by weight hyaluronic acid; andbetween about 71% and 94% by weight distilled water. The ophthalmicsolution has a pH between about 6.5 and 7.5, has an osmotic pressure ofbetween about 320-350 mOsmol/kg solution, and is hypertonic.

RCE typically develops as a result of three different issues: diabetickeratrophy; neurotrophic keratrophy; and following eye surgery such asLasik surgery. The ophthalmic solutions disclosed herein can betopically administered as a prophylactic to prevent RCE from occurringand developing in people who are at risk for developing RCE.

The ophthalmic solution can be administered about every 3 to 8 hours forabout 7 to 14 days prior to an eye surgery, such as a Lasik surgery.Typically, the ophthalmic solution is administered about every 3 to 6hours for about 10 days prior to an eye surgery.

The ophthalmic solution may be administered about 3 to 10 times dailyfor about 7 to 14 days prior to an eye surgery. More typically, theophthalmic solution is administered at least 5 times daily for at least10 days prior to an eye surgery.

The ophthalmic solution can also be administered following an eyesurgery to prevent RCE from developing. The ophthalmic solution istopically administered about every 3 to 8 hours for about 7 to 14 daysfollowing an eye surgery.

The ophthalmic solution may be administered about 3 to 10 times dailyfor about 7 to 14 days following an eye surgery. More typically, theophthalmic solution is administered at least 5 times daily for at least10 days following an eye surgery.

The ophthalmic solution can be administered to prevent RCE fromdeveloping in people who suffer from diabetic keratrophy. The ophthalmicsolution is topically administered at least one time per day to preventRCE as a result of diabetic keratrophy. Typically, the ophthalmicsolution is administered at least three times per day. More typically,the ophthalmic solution is administered at least seven times per day.

The ophthalmic solution can be administered to prevent RCE fromdeveloping in people who suffer from neurotrophic keratrophy. Theophthalmic solution is topically administered at least one time per dayto prevent RCE as a result of neurotrophic keratrophy. Typically, theophthalmic solution is administered at least three times per day. Moretypically, the ophthalmic solution is administered at least seven timesper day.

EXAMPLES

The present invention is described in more detail with reference to thefollowing non-limiting examples, which are offered to more fullyillustrate the invention, but are not to be construed as limiting thescope thereof.

Example 1

An ophthalmic solution with the following formulation can be prepared:

TABLE 1 Compound Weight Percent (%) Dextran 70 10% NaCl 0.9%  Hyaluronicacid  1% Distilled water 88.1%   CO₂ Less than 360 ppm by weight

The ophthalmic solution has an osmolality of 350 mOsmol/kg and a pH inthe range of 7.0-7.4.

Example 2

The ophthalmic solution of Example 1 can be used topically administeredto a patient suffering from RCE. The ophthalmic solution can betopically administered directly on the eye at least 7 times per day fora period of 15 weeks.

Example 3

The ophthalmic solution of Example 1 can be used topically administeredto a patient planning to undergo Lasik eye surgery. The ophthalmicsolution can be topically administered directly on the eye at least 7times per day for a period of 10 days prior to the Lasik eye surgery.

While the invention has been described with respect to certain preferredembodiments, as will be appreciated by those skilled in the art, it isto be understood that the invention is capable of numerous changes,modifications and rearrangements, and such changes, modifications andrearrangements are intended to be covered by the following claims.

What is claimed is:
 1. A method of preventing recurrent corneal erosionof a human eye comprising: topically administering to the human eye anophthalmic solution comprising: between about 5% and 25% by weight of apolymer of glucose having an average molecular weight of between about40,000 grams per mole and about 150,000 grams per mole; between about0.5% and 2% by weight NaCl; between about 0.5% and 2% by weighthyaluronic acid; and at least about 71% by weight water; wherein theophthalmic solution has a pH between about 6.5 and 7.5, has an osmoticpressure of between about 320-350 mOsmol/kg solution, and is hypertonic.2. The method of claim 1 further comprising obtaining the ophthalmicsolution from a plastic ampoule in a sealed foil pouch; wherein thesealed foil pouch has an interior closed to the external atmosphere andprovides a carbon dioxide and oxygen barrier preventing atmosphericcarbon dioxide from entering the interior of the sealed foil pouch;wherein the sealed foil pouch is opened within about 30 days prior tothe administering.
 3. The method of claim 1, wherein the ophthalmicsolution is administered daily prior to surgery of the eye.
 4. Themethod of claim 3, wherein the ophthalmic solution is administered aboutevery 3 to 8 hours for about 7 to 14 days prior to the eye surgery. 5.The method of claim 3, wherein the ophthalmic solution is administeredabout every 3 to 4 hours for about 10 days prior to an eye surgery. 6.The method of claim 3, wherein the ophthalmic solution is administeredabout every 3 to 8 hours for about 7 to 14 days following an eyesurgery.
 7. The method of claim 1, wherein the ophthalmic solution isadministered daily for at least 10 days following an eye surgery.
 8. Themethod of claim 7 wherein the ophthalmic solution is administered atleast 5 times daily after the eye surgery.
 9. The method of claim 1,wherein the ophthalmic solution is administered at least one time perday to prevent recurrent corneal erosion as a result of diabetickeratrophy.
 10. The method of claim 1, wherein the ophthalmic solutionis administered at least one time per day to a person suffering fromdiabetic keratrophy.
 11. The method of claim 1, wherein the ophthalmicsolution is administered at least one time per day to prevent recurrentcorneal erosion as a result of neurotrophic keratrophy.
 12. The methodof claim 1, wherein the ophthalmic solution is administered at least onetime per day to a person suffering from neurotrophic keratrophy.
 13. Themethod of claim 1, wherein the polymer of glucose is dextran and has anaverage molecular weight of about 70,000 grams per mole.
 14. The methodof claim 6, wherein the ophthalmic solution comprises between about 8%and 12% by weight of dextran.
 15. The method of claim 1, wherein theophthalmic solution further comprises a preservative.
 16. The method ofclaim 15, wherein the preservative is selected from the group consistingof benzalkonium chloride, thimerosal, phenylmercuric nitrate,chlorobutanol, methyl paraben, propyl paraben, chlorhexidinedigluconate, sorbic acid and EDTA.
 17. The method of claim 1, whereinthe ophthalmic solution further comprises a buffer.
 18. The method ofclaim 1, wherein the ophthalmic solution has less than about 360 ppmcarbon dioxide.
 19. The method of claim 1, wherein the ophthalmicsolution has less than about 100 ppm carbon dioxide.
 20. The method ofclaim 1, wherein the dose of ophthalmic solution for each administrationis between about 0.2 and 0.5 ml.